Nonhuman primate model of schizophrenia using a noninvasive EEG method

Systems Neurobiology Laboratories, Salk Institute for Biological Studies, La Jolla, CA 92037.
Proceedings of the National Academy of Sciences (Impact Factor: 9.67). 08/2013; 110(38). DOI: 10.1073/pnas.1312264110
Source: PubMed


There is growing evidence that impaired sensory-processing significantly contributes to the cognitive deficits found in schizophrenia. For example, the mismatch negativity (MMN) and P3a event-related potentials (ERPs), neurophysiological indices of sensory and cognitive function, are reduced in schizophrenia patients and may be used as biomarkers of the disease. In agreement with glutamatergic theories of schizophrenia, NMDA antagonists, such as ketamine, elicit many symptoms of schizophrenia when administered to normal subjects, including reductions in the MMN and the P3a. We sought to develop a nonhuman primate (NHP) model of schizophrenia based on NMDA-receptor blockade using subanesthetic administration of ketamine. This provided neurophysiological measures of sensory and cognitive function that were directly comparable to those recorded from humans. We first developed methods that allowed recording of ERPs from humans and rhesus macaques and found homologous MMN and P3a ERPs during an auditory oddball paradigm. We then investigated the effect of ketamine on these ERPs in macaques. As found in humans with schizophrenia, as well as in normal subjects given ketamine, we observed a significant decrease in amplitude of both ERPs. Our findings suggest the potential of a pharmacologically induced model of schizophrenia in NHPs that can pave the way for EEG-guided investigations into cellular mechanisms and therapies. Furthermore, given the established link between these ERPs, the glutamatergic system, and deficits in other neuropsychiatric disorders, our model can be used to investigate a wide range of pathologies.

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    • "The most prominent findings are an increase in gammaband EEG activity (>30 Hz) (Barr et al. 2010; Sun et al. 2011) and a decrease in beta-band EEG activity (15–30 Hz) (Krishnan et al. 2005; Uhlhaas et al. 2006; Hirano et al. 2008). While EEG recordings in nonhuman primates have shown that subanaesthetics doses of ketamine reduce mismatch-negative and P3a event-related potentials (Gil-da-Costa et al. 2013), it is unknown whether ketamine also alters oscillatory potentials in the PFC. Here we investigated the effects of a subanesthetic dose of ketamine on outcome-related local field potentials (LFPs) in the macaque PFC during an antisaccade task, which requires subjects to suppress a saccade towards a flashed peripheral stimulus instead to generate a saccade to the opposite direction (Munoz and Everling 2004). "
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    ABSTRACT: A subanesthetic dose of the noncompetitive N-methyl-d-aspartate receptor antagonist ketamine is known to induce a schizophrenia-like phenotype in humans and nonhuman primates alike. The transient behavioral changes mimic the positive, negative, and cognitive symptoms of the disease but the neural mechanisms behind these changes are poorly understood. A growing body of evidence indicates that the cognitive control processes associated with prefrontal cortex (PFC) regions relies on groups of neurons synchronizing at narrow-band frequencies measurable in the local field potential (LFP). Here, we recorded LFPs from the caudo-lateral PFC of 2 macaque monkeys performing an antisaccade task, which requires the suppression of an automatic saccade toward a stimulus and the initiation of a goal-directed saccade in the opposite direction. Preketamine injection activity showed significant differences in a narrow 20-30 Hz beta frequency band between correct and error trials in the postsaccade response epoch. Ketamine significantly impaired the animals' performance and was associated with a loss of the differences in outcome-specific beta-band power. Instead, we observed a large increase in high-gamma-band activity. Our results suggest that the PFC employs beta-band synchronization to prepare for top-down cognitive control of saccades and the monitoring of task outcome. © The Author 2015. Published by Oxford University Press. All rights reserved. For Permissions, please e-mail:
    Cerebral Cortex 06/2015; DOI:10.1093/cercor/bhv128 · 8.67 Impact Factor
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    • "Attenuation of MMN by NMDA antagonists has been an important pharmacological validation ever since it was first demonstrated in monkeys with PCP (28), and subsequently replicated in multiple species including human, primate, and rodent (5, 30, 31, 33, 56, 76, 77). Moreover, ketamine, a fast acting, non-selective NMDA channel blocker with rapid pharmacokinetics has been frequently studied for its effects on MMN in healthy humans. "
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    ABSTRACT: Schizophrenia patients exhibit a decreased ability to detect change in their auditory environ-ment as measured by auditory event-related potentials (ERP) such as mismatch negativity. This deficit has been linked to abnormal NMDA neurotransmission since, among other observations, non-selective channel blockers of NMDA reliably diminish automatic deviance detection in human subjects as well as in animal models. Recent molecular and functional evidence links NR2B receptor subtype to aberrant NMDA transmission in schizophrenia. However, it is unknown if NR2B receptors participate in pre-attentive deviance detec-tion. We recorded ERP from the vertex of freely behaving rats in response to frequency mismatch protocols. We saw a robust increase in N1 response to deviants compared to standard as well as control stimuli indicating true deviance detection. Moreover, the increased negativity was highly sensitive to deviant probability. Next, we tested the effect of a non-selective NMDA channel blocker (ketamine, 30 mg/kg) and a highly selective NR2B antagonist, CP-101,606 (10 or 30 mg/kg) on deviance detection. Ketamine attenu-ated deviance mainly by increasing the amplitude of the standard ERP. Amplitude and/or latency of several ERP components were also markedly affected. In contrast, CP-101,606 robustly and dose-dependently inhibited the deviant's N1 amplitude, and as a consequence, completely abolished deviance detection. No other ERPs or components were affected. Thus, we report first evidence that NR2B receptors robustly participate in processes of automatic deviance detection in a rodent model. Lastly, our model demonstrates a path forward to test specific pharmacological hypotheses using translational endpoints relevant to aberrant sensory processing in schizophrenia.
    Frontiers in Psychiatry 08/2014; 5. DOI:10.3389/fpsyt.2014.00096
    • "Of course, the findings of these studies do not necessarily count against a sensory memory-based interpretation of the human MMN, which may be species-specific or may originate from brain regions outside of A1-notwithstanding its localization to A1 in several human studies (e.g., Hari et al. 1984; Giard et al. 1990; Molholm et al. 2005). On the other hand, insofar as the macaque is considered a good animal model for understanding the neural bases of the scalp-recorded MMN in humans (Javitt et al. 1992, 1994; Gil-da-Costa et al. 2013), and to the extent that intracortical AEPs elicited by oddball sequences in monkey A1 within the latency range of the human MMN are modulated by SSA (Fishman and Steinschneider 2012) and are volumeconducted to fronto-central regions of the scalp (Arezzo et al. 1975; Javitt et al. 1992), these findings do support (at least indirectly) a contribution of SSA to the MMN recorded from the scalp in humans. Additional recordings of ERPs from the scalp and dural surface in macaques, elicited by both oddball and appropriate control stimuli, are needed in order to more firmly establish this conclusion, however. "
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    ABSTRACT: Abstract The mismatch negativity (MMN) is a pre-attentive auditory event-related potential (ERP) component that is elicited by a change in a repetitive acoustic pattern. It is obtained by subtracting responses evoked by frequent 'standard' sounds from responses evoked by infrequent 'deviant' sounds that differ from the standards along some acoustic dimension, e.g., frequency, intensity, or duration, or abstract feature. The MMN has been attributed to neural generators within the temporal and frontal lobes. The mechanisms and meaning of the MMN continue to be debated. Two dominant explanations for the MMN have been proposed. According to the "neural adaptation" hypothesis, repeated presentation of the standards results in adapted (i.e., attenuated) responses of feature-selective neurons in auditory cortex. Rare deviant sounds activate neurons that are less adapted than those stimulated by the frequent standard sounds, and thus elicit a larger 'obligatory' response, which yields the MMN following the subtraction procedure. In contrast, according to the "sensory memory" hypothesis, the MMN is a 'novel' (non-obligatory) ERP component that reflects a deviation between properties of an incoming sound and those of a neural 'memory trace' established by the preceding standard sounds. Here, we provide a selective review of studies which are relevant to the controversy between proponents of these two interpretations of the MMN. We also present preliminary neurophysiological data from monkey auditory cortex with potential implications for the debate. We conclude that the mechanisms and meaning of the MMN are still unresolved and offer remarks on how to make progress on these important issues.
    Brain Topography 07/2014; 27(4):500-526. · 3.47 Impact Factor
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